CD70-CD27 Axis in Cancer: CAR-T, ADC and Antibody Research

Table of Contents

• What Is the CD70-CD27 Axis?
• Physiological CD70 and CD27 Signaling
• Dysregulated CD70 Expression in Cancer
• Why CD70 Is an Attractive Tumor Target
• CD70-Directed Antibody Strategies
• CD70 and Antibody-Drug Conjugates
• CD70-Targeted CAR-T Research
• Bispecific and Combination Approaches
• Challenges in CD70 Targeting
• Assays for CD70 Drug Development
• Selecting Recombinant CD70 Proteins

What Is the CD70-CD27 Axis?

CD70 is a member of the tumor necrosis factor ligand family. Its receptor CD27 is expressed on several lymphocyte populations and contributes to immune-cell activation, survival and differentiation.

In normal immune biology, CD70 expression is tightly regulated and usually transient.

This makes CD70 unusual among CD antigens: instead of being constitutively abundant on resting healthy tissues, it is often induced after immune activation.

In several malignancies, however, CD70 can become persistently expressed.

This difference between transient normal expression and sustained tumor-associated expression has made CD70 an important research target.

Physiological CD70 and CD27 Signaling

CD27 is a costimulatory receptor of the TNF receptor superfamily.

Interaction with CD70 can support:

• T-cell expansion;
• survival;
• memory formation;
• B-cell responses;
• NK-cell activity under selected conditions.

The duration of signaling matters.

Short, regulated CD70-CD27 interaction can support productive immune responses, whereas chronic stimulation may contribute to immune dysfunction or altered lymphocyte differentiation.

Therefore, CD70 cannot be understood only as a tumor-surface marker. Its signaling biology is also relevant.

Fig 1. Physiological Versus Persistent CD70 Signaling

Dysregulated CD70 Expression in Cancer

Aberrant CD70 expression has been reported in hematologic malignancies and solid tumors.

Examples include:

• renal-cell carcinoma;
• selected lymphomas;
• leukemias;
• nasopharyngeal carcinoma;
• subsets of other solid tumors.

Expression varies considerably by tumor type and patient.

This is important for biomarker-driven development. A CD70-directed therapy is unlikely to behave uniformly across diseases with very different antigen density and distribution.

Assessment should ideally consider:

• percentage of positive tumor cells;
• antigen density per cell;
• intratumoral heterogeneity;
• expression on stromal or immune populations;
• change after treatment.

Why CD70 Is an Attractive Tumor Target

CD70 has several characteristics favorable for targeted drug development.

CD70 Feature	Potential Value
Surface expression	Accessible to antibodies and CARs
Restricted resting-tissue expression	Potential therapeutic window
High expression in selected tumors	Supports biomarker-directed strategies
Ligand-receptor biology	Enables functional pathway studies
Potential internalization	Relevant to some ADC formats

However, activated normal immune cells can express CD70. Therefore, "restricted expression" should not be interpreted as complete tumor specificity.

CD70-Directed Antibody Strategies

Monoclonal antibodies can be designed with several goals.

Blocking CD70-CD27 Signaling

An antibody can interfere with ligand-receptor interaction.

Recruiting Effector Functions

Appropriate Fc design may support antibody-dependent cellular cytotoxicity or phagocytosis.

Target Delivery

CD70 can act as a targeting address for conjugated payloads or engineered molecules.

The desired antibody properties depend on the intended mechanism.

A blocking antibody optimized for receptor inhibition may differ from an antibody intended primarily for Fc-mediated cell killing.

CD70 and Antibody-Drug Conjugates

ADC development requires additional target features beyond antibody binding.

After an ADC binds the tumor surface, efficient internalization and trafficking can be important for delivering payload to the appropriate intracellular compartment.

Relevant CD70 considerations include:

• target density;
• internalization kinetics;
• recycling;
• epitope location;
• antigen modulation;
• heterogeneity.

A high-affinity antibody is not necessarily the best ADC if the antigen-antibody complex traffics inefficiently.

CD70-Targeted CAR-T Research

CD70 has attracted substantial interest as a CAR-T target.

The rationale is particularly strong in malignancies with high CD70 expression and limited effective treatment options.

In 2026, results from the Phase I TRAVERSE study of an allogeneic CD70-targeted CAR-T product in advanced clear-cell renal-cell carcinoma were reported in Journal of Clinical Oncology.

This study is important because it demonstrates continued clinical investigation of CD70-directed cellular therapy in a solid tumor.

However, it should be described accurately: the study represents early-phase clinical evidence, not establishment of CD70 CAR-T as standard therapy.

Fig 2. CD70-Directed Therapeutic Modalities

Bispecific and Combination Approaches

Bispecific molecules offer another strategy.

One arm can recognize CD70 while another recruits an immune effector molecule or cell.

Potential advantages include localized immune activation and increased functional avidity.

Combination approaches may also attempt to address immunosuppression in the tumor microenvironment.

The most appropriate strategy depends on tumor type and CD70 distribution.

Challenges in CD70 Targeting

Antigen Heterogeneity

Not every tumor cell may express equal CD70 levels.

A therapy that eliminates CD70-high cells could select for antigen-low populations.

Expression on Activated Immune Cells

Activated T or B cells may express CD70, raising questions about immune-cell targeting.

Antigen Modulation

Surface expression can change after treatment.

Cross-Species Differences

An antibody optimized for human CD70 may not bind the corresponding animal ortholog.

Modality-Specific Requirements

CAR-T, ADC and antibody programs need different target characteristics.

Challenge	mAb	ADC	CAR-T
Surface density	Important	Important	Often critical
Internalization	Variable	Critical	Not generally required
Normal immune-cell expression	Important	Important	Critical
Antigen heterogeneity	Important	Important	Critical

Assays for CD70 Drug Development

A robust CD70 program should include complementary biochemical and cellular assays.

Target Expression

Flow cytometry, immunohistochemistry and quantitative protein measurements help establish the biological opportunity.

Direct Binding

ELISA, SPR and BLI can measure antibody or receptor binding to recombinant CD70 antigen.

CD70-CD27 Competition

Competition assays determine whether a candidate disrupts ligand-receptor interaction.

Cell-Surface Binding

Native cell assays confirm recognition of membrane CD70.

Internalization

Particularly important for ADC research.

Cytotoxicity

CAR-T and effector-function studies require target-density-dependent functional assays.

Cross-Species Testing

Human, mouse and nonhuman-primate CD70 proteins can help establish translational relevance.

Fig 3. CD70 Target-Validation Workflow

Selecting Recombinant CD70 Proteins

CD70 is a trimeric TNF-family ligand in its native biological context, so recombinant format can influence binding behavior.

Researchers should consider:

Domain Design

The extracellular domain should include the biologically relevant receptor-binding region.

Oligomerization

Some experimental formats may benefit from multimeric presentation, while quantitative affinity measurements may require careful control of avidity.

Fc Tag

Fc fusion can improve stability and simplify capture but produces higher-order presentation.

His Tag

A relatively small tag can be useful for biochemical characterization.

Biotinylation

Site-specific biotinylated proteins are convenient for SPR/BLI or high-throughput screening.

Species

Matched orthologs can support preclinical model selection.

Using several recombinant CD antigen proteins with consistent format can be especially valuable for human-versus-animal cross-reactivity studies.

Key Takeaway

CD70 is normally expressed transiently after immune activation but is persistently overexpressed in several malignancies. This difference has made CD70 an attractive target for antibodies, ADCs and CAR-T cells, although antigen heterogeneity and expression on activated normal immune cells remain important development challenges.

References

• Sam I, Ben Hamouda N, Alkatrib M, et al. The CD70-CD27 Axis in Cancer Immunotherapy: Predictive Biomarker and Therapeutic Target. Clin Cancer Res. 2025;31(14):2872–2881. doi:10.1158/1078-0432.CCR-24-2668.
• Wei W, Grünwald V, Herrmann K. CD70-Targeted Cancer Theranostics: Progress and Challenges. Med. 2025;6(8):100671. doi:10.1016/j.medj.2025.100671.
• Srour SA, Chahoud J, Drakaki A, et al. Allogeneic CD70-Targeted Chimeric Antigen Receptor T-Cell Therapy for Advanced Renal Cell Carcinoma: Results From the Phase I TRAVERSE Trial. J Clin Oncol. 2026;44(24):2329–2340. doi:10.1200/JCO-26-00388.
• van de Ven K, Borst J. Targeting the T-Cell Co-Stimulatory CD27/CD70 Pathway in Cancer Immunotherapy: Rationale and Potential. Immunotherapy. 2015;7(6):655–667. doi:10.2217/imt.15.32.